A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with dysmorphic facies and variable seizures (NEDDFAS) is caused by homozygous mutation in the EMC10 gene (614545) on chromosome 19q13.

Neurodevelopmental disorder with dysmorphic facies and variable seizures (NEDDFAS) is an autosomal recessive disorder characterized by global developmental delay apparent in early childhood. Patients have mildly impaired intellectual development, often with speech delay or behavioral abnormalities. Some may have seizures. Most have nonspecific dysmorphic facial features. Additional findings may include brain imaging abnormalities, mild skeletal defects, and renal abnormalities, although the renal anomalies may be unrelated (summary by Shao et al., 2021).

Umair et al. (2020) reported a brother and sister, born of consanguineous Saudi Arab parents, with a neurodevelopmental disorder. The patients, who were 14 and 11 years old, respectively, presented in early childhood with global developmental delay manifest mainly as speech delay. They later developed anxiety with poor sleep and onset of repetitive stereotypic movements and tics, such as blinking, nystagmus, and head nodding. They both attended special schools, but showed deficits in mathematics and memory. IQ was measured at 69 and 76, respectively. One sib had isolated febrile seizures at 3.5 years. They had normal growth parameters with subtle dysmorphic features, including triangular face, frontal bossing, synophrys, crowded teeth, and mild hirsutism. Brain imaging was normal.

Shao et al. (2021) reported 13 patients from 7 unrelated consanguineous families of Middle Eastern descent with NEDDFAS. The patients were ascertained from various centers through the GeneMatcher Program. Twelve patients were between 5 and 27 years of age; the remaining patient was 3 months old. All had global developmental delay with impaired intellectual development and often abnormal behavior with poor social skills. Six patients had variable types of seizures. Brain imaging was abnormal in most patients, although there were different findings, such as thin corpus callosum, cerebellar tonsillar ectopia, Chiari I malformation, delayed myelination, enlarged ventricles, and gray matter heterotopia. Four patients presented with fetal polyhydramnios, and 2 of those had infantile polyuria. Four had medullary nephrocalcinosis, 3 had renal cysts, 2 had hydronephrosis, and a 22-year-old was noted to have end-stage renal disease requiring kidney transplantation. More variable features, observed in about half of patients, included failure to thrive, cubitus valgus, hernia, and arachnodactyly. Dysmorphic facial features were common, although there was no clear pattern. These included long face, pointed chin, and curly hair. Neurologic symptoms appeared to be static or nonprogressive.

Kaiyrzhanov et al. (2022) reported 10 patients from 6 unrelated consanguineous families with NEDDFAS. The average age of the patients was 9.5 years. All 10 patients had global developmental delay or impaired intellectual development ranging from mild to severe, and 5 patients had microcephaly. Other neurologic findings included axial hypotonia (4/10), peripheral hypotonia (5/10), truncal ataxia (3/10), dysarthria (7/10), and hyperkinetic movements (4/10). Two patients had congenital heart disease. One sib pair had elevated parathyroid hormone levels. The most common facial dysmorphisms included long face, broad chin, synophrys, broad nasal tip, and thick lower lip vermilion.

The transmission pattern of NEDDFAS in the families reported by Umair et al. (2020) and Shao et al. (2021) was consistent with autosomal recessive inheritance.

In 2 sibs, born of consanguineous Arab parents, with NEDDFAS, Umair et al. (2020) identified a homozygous splice site mutation in the EMC10 gene (614545.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. RT-PCR analysis of patient cells showed decreased EMC10 mRNA levels compared to controls.

In 12 patients from 7 unrelated consanguineous families of Middle Eastern descent with NEDDFAS, Shao et al. (2021) identified a homozygous frameshift mutation in the EMA10 gene (614545.0002). The mutation, which was found by whole-exome or whole-genome sequencing at various centers, was confirmed by Sanger sequencing and segregated with the disorder in the families. It was not present in the homozygous state in public databases. Haplotype analysis identified 2 distinct haplotypes among the families, suggesting that the mutation occurred in a hotspot; the deletion was within a homopolymeric repeat sequence that predisposes to DNA replication errors. Studies of cells derived from some patients showed reduced but not absent EMC10 expression, suggesting that the mutation results in an unstable protein. The mutation resulted in a putative truncated protein of 103 amino acids in length and was predicted to abolish the C-terminal region that interacts with core EMC proteins. In vitro functional expression studies in HeLa cells transfected with the mutation showed that the mutant protein was unstable due to proteasomal degradation. Shao et al. (2021) concluded that the mutation resulted in a loss of EMC10 function, which may have detrimental effects on transmembrane protein dynamics in various cell types.

Kaiyrzhanov et al. (2022) identified homozygous mutations in the EMC10 gene in 10 patients from 6 unrelated consanguineous families. Five of the mutations were novel (614545.0003-614545.0007) and one was previously identified (614545.0002). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. The mutations were either absent or present at a rare allelic frequency in multiple public and private variant databases.

Shao et al. (2021) noted that Emc10-null mice exhibit neurologic and behavioral abnormalities, including abnormal vocalization, gait, activity, and anxiety-related mannerisms as well as defects in cognitive processes, such as memory and learning.